Drug Class Review Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) Inhibitors

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1 Drug Class Review Proprotein Convertase Subtilisin Kexin type 9 (PCSK9) Inhibitors Final Original Report July 2015 The purpose of reports is to make available information regarding the comparative clinical effectiveness and harms of different drugs. Reports are not usage guidelines, nor should they be read as an endorsement of or recommendation for any particular drug, use, or approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports. Kim Peterson, MS Brittany Holzhammer, MPH Marian McDonagh, PharmD Marian McDonagh, PharmD, Principal Investigator Pacific Northwest Evidence-based Practice Center Roger Chou, MD, Director Marian McDonagh, PharmD, Associate Director Copyright 2015 by Oregon Health & Science University Portland, Oregon All rights reserved.

2 INTRODUCTION HMG-CoA reductase inhibitors, or statins, have been the primary therapeutic intervention for hypercholesterolemia for decades. They have been successful in reducing the risk of major cardiovascular (CV) events and mortality in a wide range of at-risk individuals. However, statins (alone or in combination with other lipid-lowering therapies, such as ) are not always adequate in reducing cholesterol levels in some patients, even at higher doses (e.g., patients with heterozygous hypercholesterolemia). Additionally, some patients cannot tolerate statins. Within the last decade, the relationship between proprotein convertase subtilisin/kexin type 9 (PCSK9) and cholesterol metabolism has been increasingly studied. PCSK9 signals the degradation of the low-density lipoprotein receptor, which causes levels plasma low-density lipoprotein cholesterol to increase. Monoclonal antibodies directed at inhibiting PCSK9 are undergoing development as novel therapies in response to the therapeutic gaps posed by current standard therapies to treat hypercholesterolemia. Scope and Key Questions Currently, there are three PCSK9 inhibitors in phase III testing (Table A), which are the focus of this review. These interventions have not yet been approved by the U.S. Food and Drug Administration. The purpose of this review is to compare the benefits and harms of these drugs, with or without other lipid lowering drugs, with emphasis on health outcomes and longer-term harms. Table A. PCSK9 Inhibitors Included in this Report Generic Name Company Code Phase of Development BLA Submitted Estimated FDA Approval Evolocumab AMG 145 Phase II/III 8/28/14 Summer 2015 Alirocumab SAR Phase III 11/27/2014 7/24/2015 (REGN727) Bococizumab RN316 (PF ) Phase III Unclear 2016 Abbreviations: BLA, biologics license application; FDA, U.S. Food & Drug Administration In consultation with participating organizations, the Pacific Northwest Evidence-based Practice Center drafted Key Questions and inclusion criteria reflecting populations, drugs, and outcome measures of interest to clinicians and patients. The following Key Questions were approved to guide this review: 1. What are the comparative benefits and harms of PCSK9 inhibitors in patients with heterozygous and homozygous familial hypercholesterolemia? 2. What are the comparative benefits and harms of PCSK9 inhibitors in patients with hypercholesterolemia who are unable to use statins due to intolerance or any other reasons? 3. What are the comparative benefits and harms of PCSK9 inhibitors in patients with nonfamilial hypercholesterolemia who have not achieved LDL-C <100 mg/dl or <70 mg/dl with their current lipid lowering regimen (e.g., statin, with or without, etc.)? PCSK9 Inhibitors 2 of 9

3 4. Do the comparative benefits and harms of PCSK9 inhibitors differ when used in different patient subgroups based on demographics, socioeconomic status, other medications, or comorbidities? METHODS To identify relevant studies, we searched Ovid MEDLINE (through February Week ), the Cochrane Database of Systematic Reviews (2009 through 2015), the Cochrane Central Register of Controlled Trials (2009 through January 2015), and Scopus (2010 through 2015) using names of included drugs as search terms. We attempted to identify additional studies through hand searches of reference lists of included studies and reviews. In addition, we searched ClinicalTrials.gov for unpublished results and additional publications. Finally, we requested dossiers of published and unpublished information from the relevant pharmaceutical companies for this review. All received dossiers were screened for studies or data not found through other searches. We assessed risk of bias (quality rating) of trials based on predefined criteria developed by the United States Preventive Services Task Force (ratings: good-fair-poor) and the National Health Service Centre for Reviews and Dissemination. We graded strength of evidence based on the guidance established for the Evidence-based Practice Center Program of the Agency for Healthcare Research and Quality. RESULTS Of 205 citations identified from electronic databases, 1 pharmaceutical manufacturer dossier submission, ClinicalTrials.gov, suggestions in public comments on the draft report and hand searches, we included 17 trials. We identified no completed studies with health outcomes as primary outcomes for alirocumab, bococizumab or evolocumab, but we identified ongoing studies with such primary outcomes for evolocumab (FOURIER) and for bococizumab (SPIRE-1 and SPIRE-2) with estimated completion dates in There were no published trials of bococizumab, despite 5 completed trials identified in ClinicalTrials.gov, 4 with completion dates between October 2011 and October There were no completed or ongoing studies that directly compared different PCSK9 inhibitors. The evidence is summarized below first by drug and then by population/key Question, and in the Summary Table (Table B). Part I. Evidence for Evolocumab Heterozygous Familial Hypercholesterolemia Compared to placebo, there was high-strength evidence from 2, 12-week randomized controlled trials (RCTs) (fair- and good-quality, N=499) that evolocumab, dosed at 140 mg every 2 weeks to weeks, achieved a greater low-density lipoprotein cholesterol (LDL-C) reduction in patients who were largely taking a high-intensity statin plus with a greater improvement in high-density lipoprotein cholesterol (HDL-C) and no differences in harms (moderate-strength evidence). PCSK9 Inhibitors 3 of 9

4 Homozygous Familial Hypercholesterolemia Low-strength evidence based on 1 small, good-quality trial (N=50) suggested that evolocumab weeks reduced LDL-C significantly more than placebo at 12 weeks in patients taking a maximum statin dose and. There was no difference in HDL-C change and there was no difference in the percentage of patients with serious adverse events, neurocognitive events, or those withdrawing due to treatment emergent adverse events. However, compared with placebo, patients treated with evolocumab experienced fewer overall treatment emergent adverse events and potential injection-site reactions but more reports of gastroenteritis. Statin Intolerant Patients In statin-intolerant patients, 2 fair-quality 12-week RCTs (GAUSS and GAUSS-2; N=434) provided low-strength evidence that evolocumab led to a greater reduction in LDL-C when dosed at 280 mg every 4 weeks to or 140 mg every 2 weeks, while having generally similar effects on HDL-C and harms. There was also low-strength evidence from the GAUSS study (N=62) that the combination of evolocumab weeks plus 10 mg led to a greater percent LDL-C reduction than 10 mg alone, but insufficient evidence to draw conclusions on other outcomes. Patients Not Achieving LDL-C <100 mg/dl or <70 mg/dl While on Treatment for Hypercholesterolemia Evolocumab Compared with Ezetimibe (Both with Statin Therapy) In a comparison of evolocumab and (both with statin therapy), the LAPLACE-2 study (N=329), provided low-strength evidence that when added to either atorvastatin 10 mg or 80 mg, compared to 10 mg, evolocumab 420 mg monthly resulted in higher rates of meeting an LDL-C target of <70 mg/dl at 12 weeks, with similar rates of patients with overall adverse events. This study provided insufficient evidence to draw conclusions about HDL-C or serious adverse events or withdrawal due to adverse events, due to the small magnitude of change or event rates. Evolocumab Compared with Placebo in Patients with Varying CV Risk In short-term comparisons of evolocumab and placebo, LAPLACE-TIMI 57 AND LAPLACE-2 (N=996 for placebo comparison) provided high-strength evidence that at 12 weeks in patients with varying risk levels and not meeting LDL-C targets, significantly more patients taking evolocumab 420 mg monthly than taking placebo (both with statin therapy) achieved an LDL-C of <70 mg/dl, and had greater percent reduction in LDL-C. There was also moderate-strength evidence of modest HDL-C increases with evolocumab 420 mg monthly, and moderate- to highstrength evidence of no differences in harms outcomes. Based on 1 good quality trial longer-term (N=901; 52 weeks) there was moderatestrength evidence that evolocumab 420 mg given every 4 weeks also resulted in significantly more patients achieving a goal of LDL-C <70 mg/dl compared with placebo, low-strength evidence of a modest increase in HDL-C, and evidence of no difference in harms (moderate- and high-strength depending on outcome). Clinically important and statistically significant differences were seen in all CV risk subgroups. PCSK9 Inhibitors 4 of 9

5 Evolocumab Compared with Placebo in Patients with High CV Risk In patients with high CV risk, a small 12 week (N=104 for placebo comparison) study provided low-strength evidence that evolocumab 420 mg monthly resulted in higher rates of meeting LDL-C target of both <100 mg/dl and <70 mg/dl when added to statins in Japanese patients, compared to placebo. There was greater mean change in LDL-C, but insufficient evidence to draw conclusions about other outcomes. Mixed Populations: Heterozygous Familial, Statin-Intolerant, and Not At Target There was moderate-strength evidence, based on a pooled analysis of 2 open-label extension studies (OSLER 1 and 2) of patients completing 1 of 12 previous trials (patients not at target, with heterozygous familial hypercholesterolemia, or statin intolerance; N=4,465), that evolocumab 420 mg monthly or 140 mg every 2 weeks (plus standard care primarily statins) reduced LDL-C by 61% more than standard care alone at 12 weeks. This reduction was largely sustained at 48 weeks (58.4% more than usual care at week 48). These studies also provided lowstrength evidence of a greater proportion of patients meeting an LDL-C goal of <100 mg/dl or <70 mg/dl and a greater increase in HDL-C at 12 weeks than with standard therapy alone. CV events were reported as secondary or post-hoc outcomes but evidence is insufficient to draw conclusions. There was low-strength evidence that slightly more patients on evolocumab experienced any adverse event at 12 weeks compared with statins alone, without differences in serious adverse events, but insufficient evidence to draw conclusions about other adverse event outcomes. Part II. Evidence for Alirocumab Heterozygous Familial Hypercholesterolemia Compared to placebo, there was low-strength evidence that alirocumab achieved a higher LDL-C reduction in patients taking a maximum statin dose plus based on 1 fair-quality trial (N=77), with similar effects on HDL-C, but insufficient evidence to draw conclusions about harms. Evidence on alirocumab compared with placebo in patients taking a low- to moderateintensity statin was insufficient (1 fair-quality RCT, N=22). Homozygous Familial Hypercholesterolemia No evidence for alirocumab. Statin Intolerant Patients No evidence for alirocumab. Patients Not Achieving LDL-C <100 mg/dl or <70 mg/dl While on Treatment for Hypercholesterolemia Alirocumab versus Placebo in Average-Risk Patients Low-strength evidence from 2 small (N=154) fair-quality RCTs indicated that in patients stabilized on statins who had not achieved an LDL-C of <100 mg/dl, alirocumab 150 mg subcutaneously every 2 weeks for 8 to 10 weeks resulted in significantly more patients achieving study goal (LDL-C <100 mg/dl) and greater percent reductions (49% to 67% more) than statins alone. Evidence on adverse events and in subgroups, compared with statins alone, was insufficient due to small sample sizes. PCSK9 Inhibitors 5 of 9

6 Alirocumab versus Ezetimibe in High-Risk Patients Moderate-strength evidence based on a good-quality trial (ODYSSEY COMBO, N=720), that alirocumab, 75 to 150 mg given every 2 weeks, resulted in a higher proportion of patients with high CV risk reaching study goal of LDL-C <70 mg/dl at 24 weeks (RR, 1.70; 95% CI, 1.46 to 1.95) than 10 mg. Similarly, the difference in the percent change in LDL-C at 24 weeks was -29.8% (P<0.0001) and the difference in change in HDL-C was 8.1% (mean baseline LDL-C 106 mg/dl; P<0.0001). Alirocumab versus Placebo in High-Risk Patients Based on 2 trials (ODYSSEY COMBO I and ODYSSEY Long-Term; N =2656), there was highstrength evidence that alirocumab, 75 to 150 mg given every 2 weeks, resulted in a higher proportion of patients with high CV risk reaching study goal of LDL-C <70 mg/dl at 24 weeks than placebo (pooled RR, 9.65; 95% CI, 7.7 to 12.0). The difference in percent reduction in LDL-C (-45.9% to -61.9%, P<0.001; mean baseline LDL-C range 100 to 123 mg/dl) and HDL- C (7.3% to 7.6%, P<0.001) were also greater. There was moderate- and low-strength evidence of no difference in CV events between alirocumab and at 52 weeks or between alirocumab and placebo at 52 to 78 weeks (all with concomitant stain therapy). Moderate- and low-strength evidence found no differences in harms between alirocumab and or placebo (based on 3 trials), except for slightly more frequent injection site reactions with alirocumab in 1 study. Part III. Evidence for Bococizumab No completed studies. PCSK9 Inhibitors 6 of 9

7 OVERALL SUMMARY Evolocumab and alirocumab both had evidence of large LDL-C reductions, with few differences in adverse event outcomes compared with placebo or. The strongest evidence (high-strength) for evolocumab was in heterozygous familial hypercholesterolemia and those at average CV risk who had not achieved LDL-C of <100 mg/dl or <70 mg/dl with primarily statin-based treatment. For alirocumab, the strongest evidence (high-strength) was in patients at high CV risk who had not achieved LDL-C of <100 mg/dl or <70 mg/dl with primarily statin-based treatment. Important questions remain about the effects of PCSK9 inhibitors on health outcomes and effects with longer-term use. Table B. Summary of the evidence by drug and population Population Study N Patient N Evolocumab Concomitant lipid therapy PCSK9 inhibitor Dose Baseline LDL-C (mg/dl) Heterozygous Familial Hypercholesterolemia: 12 wks N=499 High-intensity statin mg every 2 wks to 420 mg every 4 wks Homozygous Familial Hypercholesterolemia: 12 wks 1 RCT N=50 wks High-intensity statin + Unable to use statins: 12 wks N=496 N/A 140 mg every 2 wks or 280 mg, 350, or 420 mg given every 4 wks (vs. 10 mg) Difference in LDL-C change Difference in % meeting goal 150 to % to -61% vs. placebo % (95% CI, to -19.2) vs. placebo 192 to % (95% CI, -34.1% to -17.9%) for 280 mg every 4 wks to -38% (95% CI, to -32.4) for 140 mg every 2 wks (vs. ) HDL-C 6.8% (P<0.01) to 9.2% (95% CI, +4.7% to +13.7%) Evolocumab reduced HDL-C by 0.1% vs. placebo (NS) Differences favored evolocumab for all doses (3.6% to 8.5%) Cardiovascular events Harms No differences No differences or lower rates of most harms, except more gastroenteritis No difference in overall AEs and SAEs. Significantly lower WAEs with evolocumab (3% vs. 12%). No neurocognitive events and too few injection site reactions to draw conclusions. to PCSK9 Inhibitors 7 of 9

8 Population Study N Patient N Concomitant lipid therapy Ezetimibe 10 mg PCSK9 inhibitor Dose wks Baseline LDL-C (mg/dl) Not achieved LDL-C <100 mg/dl or <70 mg/dl : wks Patients with varying risk of CV events: wks Statin, range of doses according to risk level wks (vs. placebo) N=1,375 Patients with high risk of CV events: 12 wks N=1,375 Statin, range of doses wks (vs. placebo or ) Mixed population with extended duration: wks 2 extension RCTs N=4,465 Usual care (primarily statins) wks Difference in LDL-C change Difference in % meeting goal -47% (95% CI, -53.7% to -40.8%) 104 Vs. placebo 52 wks: -57% (+/- 2.1 sd) LDL goal <70: 82.3% vs. 6.4% (P<0.0001) 12 wks: -53% to -70.5% vs. placebo LDL goal <70: 71.8% to 94.5% vs % 139 vs. placebo; 126 to 129 or 92 to 94 vs % (P<0.001) LDL goal <100: 96% vs. 1% (P<0.001) LDL goal <70: 82% vs. 0% (P<0.001) Vs. : LDL goal <70: 86% to 95% vs. 6% to 62% 12 wks: reduction of 61% (95% CI, 59 to 63, P<0.001) LDL goal <100: 90.2% vs. 26.0% LDL goal <70: 73.6% vs. 3.8% 48 wks: 58.4% (P<0.001) and HDL-C 52 wks: 5.4% (P<0.001) 12 wks: 4.5% (95% CI, 0.4 to 8.7) to 9.1% (95% CI, 4.4 to 13.7) to 12 wks: 8.7% vs. 1.7% (P<0.001) Cardiovascular events 48 wks: any CV event (adjudicated, but not a primary outcome): HR, 0.47 (95% CI, 0.28 to 0.78) with evolocumab Harms 52 wks: no differences (vs. placebo) to 12 wks: more overall AEs (60% vs. 42%), no difference in withdrawals, serious harms, injection site reactions to no conclusions Vs. : similar rates of overall AEs, but no conclusions on other harms outcomes to 48 wks: Overall AEs: 69.2% vs. 64.8%. No difference in serious adverse events. for other harms PCSK9 Inhibitors 8 of 9

9 Population Study N Patient N Alirocumab Concomitant lipid therapy PCSK9 inhibitor Dose Baseline LDL-C (mg/dl) Heterozygous Familial Hypercholesterolemia: 12 wks N=98 High-dose statin mg, 200 mg, or 300 mg every 4 wks or 150 mg every 2 wks (vs. placebo) to Not achieved LDL-C <100 mg/dl or <70 mg/dl : weeks Patients with average risk of CV events: 10 wks Statin, range of doses 75 to 150 mg every 2 wks (vs. or placebo) to N=124 at 150 mg dose Patients with high risk of CV events: wks Vs. 1 RCT N=720 Vs. placebo N=2,656 Statin, range of doses 75 to 150 mg every 2 wks (vs. or placebo) 106 (vs. ) 100 to 123 (vs. placebo): Difference in LDL-C change Difference in % meeting goal -8% to -57% -49% to -67% LDL <100: 100% vs. 16% to 52% (150 mg every 2 wks) vs. placebo 24 wks: Vs. : -29.8% (P<0.0001) LDL goal <70: RR 1.70 (95% CI, 1.46 to 1.95) -45.9% to -61.9% (P<0.001) LDL goal <70: RR 9.65 (95% CI, 7.7 to 12.0) HDL-C NSD except for 150 mg every 2 wks: % vs % (P=0.0496) 6% to 9% over placebo 24 wks: Vs. : 8.1% over (P<0.0001) 7.3% to 7.6% over placebo (P<0.0001) Cardiovascular events 52 wks: No difference in CV events between alirocumab and 52 and 78 wks: No differences between alirocumab and placebo Harms No differences in harms outcomes between alirocumab and or placebo, except for slightly more frequent injection site reactions with alirocumab in one study. and Strength of evidence: =High; =Moderate; =Low; =Insufficient Abbreviations: AEs, adverse events; CI, confidence interval CV, cardiovascular;, not reported; NSD, no significant difference; RCT, randomized controlled trial; SAEs, serious adverse events; sd, standard deviation; WAEs, withdrawal due to adverse events; wks, weeks PCSK9 Inhibitors 9 of 9